Abstract: Deep vein thrombosis (DVT) induced pulmonary embolism (PE) causes more than 0.1 million deaths annually in the US alone. Recent innovative treatment techniques for thrombolysis, such as pharmacological dissolution or fibrinolysis and mechanical fragmentation, have showed progressive results, yet still suffer from severe limitations such as low thrombolysis efficiency and long treatment times, frequent bleeding complications, high failure rate, vein injury associated with severe regional dysfunction, recurrence, and the relatively large particle size of residual clot debris which can result in distal embolism. This has led to great interest in sonothrombolysis, the use of focused ultrasound to disrupt clots, yet current commercial sonothrombolysis systems (e.g. EKOS) are still limited by long treatment times and peripheral tissue damage due to heating and excessive acoustic exposure. More recently, our group and others have demonstrated several advances which promise to improve the performance (significantly reduced treatment time) and safety of thrombolysis using a microbubble-mediated laser ultrasound technology. We hypothesize that the development of a new approach for sonothrombolysis combining laser ultrasound, photoacoustic imaging guidance as well as cavitation-enhancing agents can substantially improve the efficacy, safety, and impact of intravascular sonothrombolysis. In this project, we develop innovative technologies from our collaborative group, each of which has shown notable advantages over current technology, and we hypothesize that together they can overcome challenges in the aforementioned embolism treatments. Specifically, a 4-French forward firing fiber optic ultrasound (FOUS) catheter will be integrated with a photoacoustic imaging system and a micro-tube for delivery of microbubbles and lytic agent (tissue-type plasminogen activator or t-PA), to achieve forward firing intravascular sonothrombolysis. The combination of microbubbles and broadband acoustic waves from FOUS is expected to achieve high lytic rate. Furthermore, our forward-firing FOUS together with photoacoustic imaging will enable ultrasound image guidance, reducing the need for fluoroscopy and improving procedure safety. The FOUS catheter will be designed, prototyped and characterized, followed by in-vitro and ex-vivo thrombolysis tests. Innovation comes from the forward-firing laser generated focused ultrasound (LGFU) approach and catheter-based photoacoustic image guidance. This approach will also reduce the dose of lytic agent, minimize physical contact with the target clot, and reduce acoustic exposure of the surrounding tissues. The proposed FOUS catheter technology will provide a new tool for accurate, fast, and safe DVT treatment.